Department of Molecular Oncology, Institute of Development, Aging and Cancer, Tohoku University, Miyagi, Japan.
Cancer Sci. 2013 Jul;104(7):871-9. doi: 10.1111/cas.12159. Epub 2013 May 2.
Most cancer cells are aneuploid, which could be caused by defects in chromosome segregation machinery. Nucleoporins (Nup) are components of the nuclear pore complex, which is essential for nuclear transport during interphase, but several nucleoporins are also known to be involved in chromosome segregation. Here we report a novel function of Nup188, one of the nucleoporins regulating chromosome segregation. Nup188 localizes to spindle poles during mitosis, through the C-terminal region of Nup188. In Nup188-depleted mitotic cells, chromosomes fail to align to the metaphase plate, which causes mitotic arrest due to the spindle assembly checkpoint. Both the middle and the C-terminal regions were required for chromosome alignment. Robust K-fibers, microtubule bundles attaching to kinetochores, were hardly formed in Nup188-depleted cells. Significantly, we found that Nup188 interacts with NuMA, which plays an instrumental role in focusing microtubules at centrosomes, and NuMA localization to spindle poles is perturbed in Nup188-depleted cells. These data suggest that Nup188 promotes chromosome alignment through K-fiber formation and recruitment of NuMA to spindle poles.
大多数癌细胞是非整倍体，这可能是由于染色体分离机制的缺陷造成的。核孔蛋白（Nup）是核孔复合体的组成部分，核孔复合体对于间期的核运输至关重要，但也有几种核孔蛋白被认为参与染色体分离。在这里，我们报告了一种调节染色体分离的核孔蛋白 Nup188 的新功能。Nup188 通过 Nup188 的 C 端区域在有丝分裂期间定位于纺锤体两极。在 Nup188 耗尽的有丝分裂细胞中，染色体不能排列到中期板上，这会由于纺锤体组装检查点而导致有丝分裂停滞。染色体排列既需要中间区域，也需要 C 端区域。在 Nup188 耗尽的细胞中，几乎没有形成强壮的 K-纤维，即附着在动粒上的微管束。重要的是，我们发现 Nup188 与 NuMA 相互作用，NuMA 在微管向中心体的聚焦中起着重要作用，并且在 Nup188 耗尽的细胞中，NuMA 定位到纺锤体两极受到干扰。这些数据表明，Nup188 通过 K-纤维的形成和将 NuMA 募集到纺锤体两极来促进染色体的排列。
